Natural history and clinical burden of moderate aortic stenosis: a systematic review and explorative meta-analysis

Aims The mortality risk of patients with moderate aortic stenosis is not well known, but recent studies suggested that it might negatively affect prognosis. We aimed to assess the natural history and clinical burden of moderate aortic stenosis and to investigate the interaction of patients’ baseline characteristics with prognosis. Methods Systematic research was conducted on PubMed. The inclusion criteria were inclusion of patients with moderate aortic stenosis; and report of the survival at 1-year follow-up (minimum). Incidence ratios related to all-cause mortality in patients and controls of each study were estimated and then pooled using a fixed effects model. All patients with mild aortic stenosis or without aortic stenosis were considered controls. Meta-regression analysis was performed to assess the impact of left ventricular ejection fraction and age on the prognosis of patients with moderate aortic stenosis. Results Fifteen studies and 11 596 patients with moderate aortic stenosis were included. All-cause mortality was significantly higher among patients with moderate aortic stenosis than in controls in all timeframes analysed (all P < 0.0001). Left ventricular ejection fraction and sex did not significantly impact on the prognosis of patients with moderate aortic stenosis (P = 0.4584 and P = 0.5792), while increasing age showed a significant interaction with mortality (estimate = 0.0067; 95% confidence interval: 0.0007–0.0127; P = 0.0323). Conclusion Moderate aortic stenosis is associated with reduced survival. Further studies are necessary to confirm the prognostic impact of this valvulopathy and the possible benefit of aortic valve replacement.


Introduction
Aortic stenosis is the most common valvulopathy in Europe and North America, and its prevalence is increasing with ageing. 1,2In fact, nowadays, calcific aortic valve disease (also known as degenerative or senile) is the most common cause of aortic stenosis in high-income countries. 3,4According to current guidelines, moderate aortic stenosis (mAS) is defined as an aortic valve area between 1 and 1.5 cm 2 , a mean pressure gradient between 20 and 40 mmHg or a peak aortic jet velocity between 3 and 4 m/s. 5Several pivotal trials revealed that severe aortic stenosis negatively affects prognosis, 6,7 and current guidelines recommend early treatment with either transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR). 1,5On the contrary, the impact of mAS has not been extensively studied, and ongoing trials are aiming at assessing if its early treatment is associated with improved outcomes. 8The aim of the present systematic research and meta-analysis is to explore the natural history and clinical burden of mAS and to investigate the interaction of baseline characteristics with the prognosis of patients with this valvular heart disease.).The following filters were applied: human species and Italian, English, French and German language.Articles were screened by title and abstract content.In addition, the reference lists of all eligible studies were screened.

Materials and methods
Articles were considered eligible if they fulfilled the following criteria: inclusion of patients with mAS; and report of the survival at 1-year follow-up (minimum).
For each study, the following information was extracted: publication data (first author, journal, publication year), study design (number of patients and controls included, subpopulations considered), population characteristics (including age, sex, BMI, comorbidities, cardiovascular risk factors, ongoing therapies, NYHA class), echocardiographic characteristics [including left ventricular ejection fraction (LVEF), mean pressure gradient, peak aortic jet velocity, aortic valve area] and outcome data [including mortality, survival, aortic stenosis progression, aortic valve replacement (AVR)].Data extraction was performed by two authors (M.M., M.G.) in parallel; all controversies were examined with a senior author (C.M.).

Statistical analysis
Continuous variables were expressed as mean AE standard deviation and categorical variables as count (%).When data were available only as median and interquartile range, mean and standard deviation were calculated according to Wan et al. 9 Baseline characteristics from each study were pooled and compared between patients with mAS and controls, obtaining pooled weighted means with 95% confidence intervals (CIs).Incidence ratios related to all-cause mortality in patients and controls of each study with 95% CIs were estimated from raw mortality data and then pooled using the fixed effects Mantel-Haenszel model. 10Meta-regression analysis was performed to assess the impact of LVEF, female sex and age on the prognosis of patients with mAS.Statistical heterogeneity was estimated by calculating the I 2 index.Heterogeneity was considered to be low for I 2 less than 25%, moderate for I 2 25-75% and high for I 2 more than 75%. 11Individuals without aortic stenosis or with mild aortic stenosis were defined as controls.Statistical significance was set at a two-sided P-value less than 0.05.Data analysis was performed in the R environment.

Results
The systematic literature search identified 1522 studies.Fifteen articles were included in this systematic review with a total of 11 596 patients with mAS (Fig. 1 and Table 1).These studies were observational with a mean follow-up ranging from 1.8 to 9.5 years.They studied the prognosis, assessing all-cause mortality, cardiovascular mortality, AVR, aortic stenosis progression, complications, hospitalization for heart failure, progression of symptoms.

Discussion
Aortic stenosis is a common disease; it is progressive nature and potentially fatal when it becomes severe.Therefore, it is recommended that physicians should screen patients and treat them early when symptoms develop, in order to avoid excess mortality.Both European and American guidelines for the management of valvular heart diseases mostly focus on severe aortic stenosis with indications for TAVI or SAVR mainly driven by age and comorbidities. 1,5Nonetheless, several small recent studies individually showed that mAS (even if asymptomatic) might negatively affect prognosis, [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] although a precise estimate of the mortality risk associated with mAS is unknown.Some older studies revealed that mAS is relatively benign, but the definition of the disease and the population affected have changed over time. 27,28r systematic review shows that mAS is not a benign disease, as these patients experience a worse prognosis compared with those with mild aortic stenosis or no aortic stenosis.In particular, we also offer a tentative estimate of the excess mortality risk, with a relative risk for death ranging from 1.43 at 1-year to 2.28 at 5-year follow-up.In fact, despite including a large number of patients in our analysis, we acknowledge that the observational nature of the studies included generates a large heterogeneity that limits the external validity of our meta-analysis, the results of which should then be interpreted as explorative.Nonetheless, our results are in line with those of another recent meta-analysis, which showed that mAS appears to be Natural history and clinical burden of moderate aortic stenosis Morelli et al. 661 associated with an excess mortality risk, which is expectedly lower than severe aortic stenosis. 29In addition to this, we explored possible interactions with other important characteristics and showed that neither LVEF nor sex significantly impacts on mortality at mid-term.This is important, as both have been associated with worse prognosis in severe aortic stenosis 30,31 but, in the context of mAS, close follow-up and early treatment, regardless of baseline characteristics, appear to be of prominent importance.Only age was associated with a significantly worse prognosis, which is biologically expected and reinforces the internal validity of our analysis.
In summary, our data highlight some important concepts about mAS.Firstly, mAS is not a benign disease and it is intrinsically associated with a higher hazard of death.In particular, the relative increase of death at 1 year suggests that mAS might have an intrinsic potential risk including rapid progression to severe aortic stenosis with early fatal outcomes.We also postulate that in some cases, especially those with low-flow low-gradient aortic stenosis due to impaired LVEF, a truly severe aortic stenosis might be erroneously downgraded to mAS and treated conservatively, despite a clear indication for intervention.The idea of aortic stenosis as a spectrum of hazard that ranges from mAS to asymptomatic severe aortic stenosis to symptomatic severe aortic stenosis is being tested also in ongoing randomized and controlled clinical trials such as the EAR-LY-TAVR trial, which is evaluating the TAVI on patients with asymptomatic severe aortic stenosis, 32 and the TAVR UNLOAD trial, which is testing TAVI on patients with mAS and heart failure with reduced LVEF. 8Our results corroborate this hypothesis and highlight that we should not neglect mAS and at least screen it for severity and symptoms.
Secondly, one could argue that, if the procedural risk is relatively low as with TAVI, a lower threshold for  15 American Journal of Cardiology 2021 738 / 9.5 Jean et al. 16 Journal of the American College of Cardiology 2021 262 No AS 2.9 Lee at al. 17 Journal of Korean Medical Science 2021 787 General population 7.7 Bae et al. 18 Heart Surgery Forum 2020 148 / 5.6 Delesalle et al. 19 American Heart Association 2019 508 / 3.9 Strange et al. 20 Journal of the American College of Cardiology 2019 3315 No AS and mild AS 3.3 Van Gils et al. 21ournal of the American College of Cardiology 2017 305 / 4.0 Romero et al. 22 American Journal of Cardiology 2014 2358 Mild AS 2.3 Yechoor et al. 23 Journal of Thoracic and Cardiovascular Surgery 2013 104 / 1.8 Rosenhek et al. 24 European Heart Journal 2004 176 / 4.0 Iivanainen et al. 25 American Journal of Cardiology 1996 26 No AS and mild AS 4.0 Kennedy et al. 26 Journal of the American College of Cardiology 1991 66 / 2.9 intervention could be applied in selected cases.This is corroborated by some retrospective studies, which showed that the AVR significantly improved the survival of patients with mAS, especially in those with impaired LVEF.16,19,22,33 Nonetheless, it should be highlighted that, if considered TAVI candidates, lifetime management considerations will be of prominent importance, as these individuals are younger (mean age: 75.7 years) and not free from coronary artery disease (prevalence: 25.7%). Moover, careful preprocedural screening is anticipated, as complications such as paravalvular leaks and conduction disturbances leading to permanent pacemaker implantations could not be tolerated in younger and more active patients with mAS (or asymptomatic severe aortic stenosis).Furthermore, also, valve deterioration and consequent need for a second (and even third) procedure during the individual's lifespan should be taken into consideration, especially in younger patients, who could outlive their transcatheter heart valve, as their life expectancy could exceed the durability of the valve bioprosthesis.34 Study limitations Some limitations should be taken into consideration. Fit, the systematic literature search was conducted on PubMed only.Second, this work included only observational studies, due to the lack of clinical trials on this topic, which limits the generalizability of our findings. Th is also testified by the high heterogeneity of our meta-analysis results, which should therefore be regarded as explorative and hypothesis-generating only.Third, some mortality rates were not explained in the text of the articles, so these data were extrapolated from Kaplan-Meier plots. Foth, Supplementary Figures 1-5  plausible and it deserves interpretation: firstly, the literature search was focused on mAS so it should not be interpreted as complete for severe aortic stenosis; secondly, due to the current management of this valvulopathy, patients with untreated mAS were compared with patients with treated severe aortic stenosis, which might account for a better prognosis in the latter group, and even reinforce our previous considerations.Finally, patients with mAS and controls differed from each other significantly: it is possible that there was a confounder associated with this valvulopathy.

Conclusion
Moderate aortic stenosis is associated with a higher allcause mortality risk; therefore, it might deserve close follow-up and further studies are necessary to confirm its prognostic importance and possible benefits of early intervention.

Table 2
Pooled characteristics of patients with moderate aortic stenosis and controls Natural history and clinical burden of moderate aortic stenosis Morelli et al. 663 , http://links.lww.com/JCM/A534 show that pooled all-cause mortality of patients with severe aortic stenosis is lower than that of patients with mAS.This result is unexpected and not biologically